Highlights from Recent Cancer Literature
Journal: Cancer Research (2011)

de Bruyn M, Wei Y, Wiersma VR, Samplonius DF, Klip HG, van der Zee AG, et al. Cell surface delivery of TRAIL strongly augments the tumoricidal activity of T cells. Clin Cancer Res 2011;17:5626–37.T cells that express the cell-surface marker CD8 have undoubted potential to recognize and destroy malignant cells expressing cognate antigens. For some human cancers, the more CD8+ T cells in a tumor microenvironment, the better the patient's prognosis. However, by the time most cancers are detected, there may not be enough of these useful cells to have a major clinical impact. One treatment approach has been to harvest T cells from a patient, expand them in the presence of a cocktail of cytokines, and return the T cells to the patient in the hope that they may generate specific anticancer immunity. Although this strategy works in some instances, it is usually ineffective, not least because the malignant cells acquire resistance to the killing methods used by CD8+ T cells. de Bruyn and colleagues have described novel methods leading to 500-fold increased killing potential of CD8+ T cells, and these novel methods are easily translatable to the clinic. This novel strategy targeted one particular killing molecule—TNF-related apoptosis-inducing ligand (TRAIL)—to the T-cell surface. This resulted in greatly enhanced ability of T cells to kill targeted malignant cell lines and primary cells from cancer patients at a ratio of 2:1 T cells to malignant cells; without TRAIL, it took a ratio of 100:1 T cells to malignant cells to achieve similar results. The authors tried 2 different approaches: (i) an anti-CD3:TRAIL, in which the anti-CD3 component also played a role in activating T cells, and in which the killing mechanism involved granzyme and perforin; and (ii) K12:TRAIL, which functioned by activation of caspases in malignant cells. Results from the in vitro and in vivo xenograft experiments suggest that anti-CD3:TRAIL may be particularly useful for ex vivo tumor cell purging of bone marrow, or for tumors in anatomically confined regions. In contrast, results from the K12:TRAIL approach show enhanced graft-versus-tumor responses without causing detrimental graft-versus-host disease. The K12:TRAIL approach could be further varied with the use of TRAIL fusion proteins incorporating other immunomodulatory ligands or antibody fragments. To this end, the authors suggest other ways to simultaneously stimulate T cells and add another killing molecule to their surface.Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 2011;20:300–14.Cells of the immune system can serve as friends or foes with regard to cancer development. A prevailing model suggests that immune surveillance is triumphant at an early stage of tumor formation, with advanced cancers generally entraining the immune system to drive malignancy. To clarify the role of immunosurveillance in breast cancer metastases, Granot and colleagues implanted breast cancers orthotopically in mice and performed microarray analyses of liver and lung tissues. A number of neutrophil-specific genes were expressed in lung, but not liver. Depletion of neutrophils blocked metastases, indicating that neutrophil seeding of the lungs blocked establishment of metastases. Subsequent experiments showed that neutrophils were entrained through secretion of CCL2, and blocked malignant cells through production of H2O2. Similar tumor-entrained neutrophils were also isolated from women with newly diagnosed breast cancer. These results suggest that neutrophils are co-opted by primary breast cancers to block spread to metastatic sites.Stacey SN, Sulem P, Jonasdottir A, Masson G, Gudmundsson J, Gudbjartsson DF, et al. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nat Genet 2011; 43:1098–103.Basal cell carcinoma is a very common skin cancer associated with sun exposure and with mutations in genes regulating Sonic Hedgehog signaling. To identify candidate susceptibility genes, Stacey and colleagues performed a genome-wide association study of 1,400 affected individuals and 30,000 controls in the Icelandic population, using single-nucleotide polypeptide arrays, with whole-genome sequencing of 460 additional individuals. They identified a strong signal (OR, 2.36; P = 5.2 × 10−17) in the 3′ untranslated region of TP53, which was subsequently confirmed in non-Icelanders, albeit at frequencies below the 0.019 level found in Icelanders. This variant, which leads to impaired 3′ processing of TP53 through modification of the polyA sequence, was also associated with susceptibility to prostate cancer (OR, 1.63; P = 1.1 × 10−4) and to glioma (OR, 2.35; P = 1.0 × 10−5), but not for breast cancer, a malignancy linked to mutation in p53, which leads to gain of function in this tumor-suppressor gene.Chen Q, Zhang XH, Massagué J. Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 2011;20:538–49.Metastatic breast carcinoma cells exhibit increased expression of vascular cell adhesion molecule-1 (VCAM-1), but the functional consequence of this increased expression has remained enigmatic. A recent report by Chen and colleagues has revealed a prosurvival function for VCAM-1–positive breast carcinoma cells in tumor microenvironments heavily infiltrated by myeloid cells, specifically macrophages expressing α4-integrins. Interaction of macrophage α4-integrin with VCAM-1 resulted in VCAM-1 membrane clustering and subsequent EZRIN-dependent triggering of AKT activation, which in turn resulted in a prosurvival signal for breast carcinoma cells that metastasized to the lung. Significantly, blockade of interaction between VCAM-1 and α4-integrin enhanced apoptotic activity after exposure to proapoptotic cytokines including TRAIL. Together, these data indicate that breast carcinoma cells metastasize in part by co-opting a physiologic mechanism that enables them to increase their survival by interacting with macrophages in their local tumor microenvironments. These results illustrate how innate immune cells can causally contribute to metastasis by providing a survival advantage to cells that carry a receptor eliciting a prosurvival advantage. Hence, targeting of tumor cell and leukocyte interactions may provide a novel approach for preventing penultimate stages of cancer progression, namely metastasis.Tran PT, Bendapudi PK, Lin HJ, Choi P, Koh S, Chen J, et al. Survival and death signals can predict tumor response to therapy after oncogene inactivation. Sci Transl Med 2011;3:103ra99.The ability to predict when targeting the inactivation of a gene product will result in tumor regression would be highly useful for development of new anticancer therapeutics. Tran and colleagues used a computational biologic approach to develop methods for predicting when malignant cells are addicted to oncogenes with the hope that this strategy could inform development and clinical use of targeted therapeutics. To start, they showed the utility of the mathematical model for predicting when oncogene inactivation would result in tumor regression, using transgenic mouse models of tumor progression to evaluate survival and death signals in malignant cells. Surprisingly, they found that both types of signals decreased upon oncogene inactivation, but the former decreased more quickly, when a tumor is poised to regress. This response was similar to the “oncogenic shock” model proposed by other investigators. Next, the investigators showed the utility of their mathematical modeling approaches to predict when inhibition of epidermal growth factor receptor activation would result in regression of tumors in patients with adenocarcinoma, thus providing an example of the increasing feasibility for in silico modeling of pathophysiologic processes. Further work is required to discern whether these approaches can be used prospectively to predict the efficacy of a targeted therapeutic, and whether they can be applied to combined therapies as well as single agents.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.